Nilotinib (Nilotinib, chemical name: 4-Methyl-3-[4-(3-pyridinyl)-2-pyrimidinyl)amino)-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluorom ethyl)phenyl]benzamide) is a high-selectivity oral tyrosine kinase inhibitor developed by Novartis. Its monohydrochloride monohydrate was approved for marketing by US FDA in October 2007, with its trade name as Tasigna. Clinically, it is used for the treatment of chronic myelocytic leukemia (CML) which is ineffective by use of imatinib mesylate. The drug can, through targeting effect, selectively inhibit tyrosinase and philadelphia chromosome positive CIVIL caused by encoding gene mutation, with a good patient tolerance, strong selectivity, and a significant curative effect.
There have been a lot of reports about the preparation method of Nilotinib, most of which relates to two important intermediates: 3-(4-methyl-1H-imidazol-1-yl)-5-trifluorom ethyl phenylamine (I) and 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino] benzoic acid(II).

The preparation of intermediate (I) mainly includes the following several synthetic routes:
Patents WO2004/00528 and WO2006/135640 reported the synthesis method of the targeted intermediate (I) through nucleophilic substitution, hydrolysis reaction, Curtius rearrangement reaction and hydrolysis reaction by using 3-fluoro-5-(trifluoromethyl)benzonitrile and 4-methyl-1H-imidazole as raw materials.

Patents WO2006/135640 and WO2006/135641 reported another synthesis method: taking 1-bromo-3-fluoro-(trifluoromethyl)benzene and 4-methyl-1H-imidazole as raw materials, to get the targeted intermediate (I) through nucleophilic substitution and hydrolysis reaction.

The above patents also reported a synthesis method of taking 1-bromo-4-fluoro-2-trifluorotoluene as raw material, and preparing the targeted intermediate (I) by nitration, reduction, and nucleophilic substitution successively.

Patents WO2006/022026, WO2008/038042 and the Chinese Journal of Pharmaceuticals (P. 17, Issue 1, Volume 44, 2013) reported a method for preparing the targeted intermediate (I) through double nitration reaction, substitution and reduction by using trifluorotoluene as raw material.

Patents WO2009/049028, WO2010/009402 and the Synthesis (P. 2121, Volume 14, 2007) reported a relatively common preparation method: taking 3-Fluorotoluene as an initial material, and preparing the targeted intermediate (I) by single nitration, bromination, reduction, condensation and substitution reaction.

By investigation of the present preparation methods of nilotinib intermediate (I), many of them have problems such as very rare raw materials, long steps, high cost and low yield, etc. Comparatively speaking, the most common method is to reduce 3-bromo-5-nitro-trifluorotoluene to get corresponding amide 3-bromo-5-trifluoromethyl-aniline, and then get the targeted product through condensation, because the activation and benzene ring after nitro is reduced to amino make it easier to achieve the subsequent condensation reaction based on the mechanism of nucleophilic substitution. This method was reported in literature up to 70%. In the research process, the inventor found that this route has a relatively high yield, but in the actual reaction process, due to different selection of temperature, type and dosage of catalyst, and acid-binding agent, the raw material's own functional group's bromine and amino will have self-coupling condensation in different extent, with over 50% coupled products, thus influencing the effect of industrialized enlargement.
To fundamentally solve the self-coupling problem of 3-bromo-5-trifluoromethyl-aniline, the best choice is to conduct condensation reaction before 3-bromo-5-nitro-trifluorotoluene is reduced, so as to get 3-(4-methyl-1H-imidazol-1-yl)-5-nitro-trifluorotoluene, then conduct reduction reaction of nitro, to get the targeted product, nilotinib intermediate (I). This new design thought overcomes the occurrence of side reaction of coupling, because nitro is unable to have self-coupling condensation reaction with bromine. However, the inactivation of nitro greatly reduces the activity of the targeted condensation reaction. Patent WO2006/135640 reported this synthetic route: under the action of catalyst and alkali, 3-bromo-5-nitro-trifluorotoluene and 4-methyl-1H-imidazole have condensation reaction, with a yield of only 20-25%, thus it further loses the value of industrial production.
Therefore, it is necessary to find a new preparation method of nilotinib intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethyl phenylamine (I), of which the raw materials are easily obtained, and it is easy to operate with few side reactions and environmental pollution.